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Role of intercellular communication in pathogenesis of diabetic retinopathy

细胞间通讯在糖尿病视网膜病变发病机制中的作用

基本信息

批准号：
10225557
负责人：
Sayon Roy
金额：
$ 43.17万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2022-04-20
项目状态：
已结题

项目摘要

Project Summary The overall goal of this research is to establish whether maintenance of connexin 43 (Cx43)-mediated gap junction intercellular communication (GJIC) and Cx43 hemichannel (HC) activity in the retinal capillaries of diabetic patients plays a protective role against the development of retinal vascular cell loss and vascular permeability associated with diabetic retinopathy (DR). Substantial evidence suggests that reduced GJIC activity in retinal vascular cells may contribute to the breakdown of homeostatic balance in DR (1-4). We have shown that the expression of Cx43, the principal gap junction protein, is downregulated in retinal vascular cells in high glucose (HG) condition with concomitant reduction in GJIC activity (3, 4) that contributes to loss of retinal vascular cells and capillary leakage. Preliminary data indicate HG reduces Cx43 HC activity and trigger apoptotic cell death (5). Recently, we observed that maintenance of cell-cell coupling inhibits HG-induced apoptosis and excess cell monolayer permeability in vitro (6). Based on these findings, we hypothesize that preventing hyperglycemia-induced Cx43 downregulation and GJIC activity would promote vascular homeostasis, restore Cx43 HC activity and Cx43 phosphorylation, ultimately preventing loss of retinal vascular cells and capillary leakage in DR. The hypothesis is supported by findings from previous funding period that showed (i) HG-induced downregulation of Cx43 expression contributes to the breakdown of endothelial barrier tight junctions by reducing ZO-1 and occludin expression (7, 8) and that restoration of Cx43 expression (7) and gap junction coupling prevents HG-induced apoptosis and cell monolayer permeability in retinal endothelial cells (6); (ii) Cx43 expression is downregulated in human retinas, and that the severity of retinal vascular cell loss is linked to the extent to which Cx43 downregulation develops (9). The hypothesis is also supported by key preliminary data that Cx43 phosphorylation is altered at s368 and s373 negatively impacting Cx43 functionality in GJIC and HC activity. Additionally, reports indicate that ZO-1, a component of the tight junction, interacts directly with Cx43 (10), and regulates Cx43-mediated GJIC activity (11, 12). Having observed ZO-1 to be reduced in retinal vascular cells by HG/diabetes (13), we propose to examine whether Cx43 downregulation, compromised GJIC, altered HC activity, and altered Cx43 phosphorylation promotes retinal vascular cell loss and tight junction dysfunction in vascular permeability. Findings are expected to provide valuable insight into a novel mechanism underlying retinal vascular cell loss and capillary leakage, and a potential strategy to prevent retinal vascular lesions in DR.

项目摘要本研究的总体目标是确定连接蛋白43（Cx43）介导的间隙的维持是否视网膜神经元细胞间连接通讯（GJIC）和Cx43半通道（HC）活性糖尿病患者的毛细血管对视网膜血管细胞损失的发展起保护作用以及与糖尿病视网膜病变（DR）相关的血管通透性。大量证据表明，视网膜血管细胞中GJIC活性的降低可能导致DR中稳态平衡的破坏（1-4）。我们已经表明，Cx43的表达，主要的间隙连接蛋白，是在高糖（HG）条件下视网膜血管细胞下调，伴随着 GJIC活性（3，4），导致视网膜血管细胞损失和毛细血管渗漏。初步数据表明HG降低Cx43 HC活性并引发凋亡性细胞死亡（5）。最近，我们观察到，维持细胞-细胞偶联抑制HG诱导的细胞凋亡和过度的细胞单层通透性，离体培养（6）。基于这些发现，我们假设预防高血糖诱导的Cx43 下调和GJIC活性可促进血管稳态，恢复Cx43 HC活性， Cx43磷酸化，最终防止DR中视网膜血管细胞的损失和毛细血管渗漏。这一假设得到了上一个供资期的研究结果的支持，这些结果表明：（i）汞引起的 Cx43表达下调导致内皮屏障紧密连接的破坏，减少ZO-1和occludin表达（7，8），恢复Cx43表达（7）和gap 连接偶联阻止HG诱导的视网膜细胞凋亡和细胞单层通透性内皮细胞（6）;（ii）Cx43表达在人视网膜中下调，视网膜病变的严重程度血管细胞损失与Cx43下调的程度有关（9）。假设也是 Cx43磷酸化在s368和s373发生负性改变，影响GJIC和HC活性中的Cx43功能。此外，报告显示，ZO-1，a 作为紧密连接的组成部分，直接与Cx43相互作用，并调节Cx43介导的GJIC 活动（11，12）。已经观察到视网膜血管细胞中的ZO-1因HG/糖尿病而减少（13），我们建议检查Cx43下调、GJIC受损、HC活性改变以及改变的Cx43磷酸化促进视网膜血管细胞损失和紧密连接功能障碍血管通透性这些发现有望为深入了解潜在的新机制提供有价值的见解。视网膜血管细胞丢失和毛细血管渗漏，以及预防视网膜血管病变的潜在策略，博士